Bone repair putty

ABSTRACT

A bone repair material is described that is of putty-like consistency, particularly useful for repairing dental bony defects such as those caused by bone loss resulting from moderate or severe periodontitis, augmenting of bony defects of the alveolar ridge, filling tooth extraction sites, or sinus elevation grafting. The repair material includes a porous, resorbable particulate that is bone-derived or derived from bone-like hydroxyapatite or synthetic hydroxyapatite; and, a resorbable carrier, such as high molecular weight polysaccharides, such as hyaluronic acid. A high concentration of particulate in the putty enhances bone repair and requires a high concentration of carrier to retain the putty at the defect site. For a particulate density of about 1.2 g/cc such as PEPGEN P-15® Bone Graft, a preferred formulation comprises about 55% percent by weight of the putty suspended in a hyaluronic acid gel of about 1.4×10 6  daltons molecular weight and a final concentration of about 56 mg/cc which material adheres to a bony periodontal defect and does not excessively expand or migrate from the defect when held in place by a conventional flap closure.

FIELD OF INVENTION

[0001] The present invention relates to improvements in bone repairmaterials employed to promote growth of bone to repair defects therein.More particularly, the bone material of the invention focuses uponenhancing treatment of dental bone defects such as bone loss frommoderate or severe periodontitis, augmenting of bony defects of thealveolar ridge, filling tooth extraction sites, or sinus elevationgrafting.

BACKGROUND OF THE INVENTION

[0002] In the repair of a dental bone defect such as periodontal boneloss, a treatment may include application of a composition orformulation to the defect site to enhance repair and bone healing. Thecomposition typically includes: (1) a particulate material to providestructural support and filling of the defect; (2) compounds ormedicaments to enhance repair of bone; and (3) a carrier system tofacilitate delivery to and retention of the composition at the defectsite for the duration of the treatment.

[0003] Selection of the particulate material depends upon its intendedfunction in the treatment, its biocompatibility with the human body andits availability. A key limitation is whether the function of thetreatment requires that the material be resorbed by natural bodilyactions or remain in place as permanent supporting structures. Manyformulations such as those described by Hubbard in U.S. Pat. No.5,922,025 and related patents intend to deliver, by injection, a tissueaugmentation material that is non-resorbable, for example comprising aceramic particulate of 15-150 μm, suspended in a resorbablepolysaccharide gel carrier, such as hyaluronic acid. The non-resorbableceramic particulate is intended to effect a one-time, permanent repairthat does not require repetitious treatments. Other such materialsinclude bioactive/biocompatible glass particulates, such as described byWalker et al in WO 91/17777, also comprising an injectable gel formed ofa hyaluronic acid, of at least 10⁶ daltons molecular weight. See alsoHench et al in U.S. Pat. No. 5,840,290 and related patents, wherein aglass particulate is said to bond to bone at the defect site, enhancingosseous ingrowth or infiltration for repair.

[0004] Where it is desired to generate new bone to repair a defect andwhere immediate and continued structural support is not a limitingfactor, regeneration of bone by natural body mechanisms is mostdesirable. The natural repair and regeneration process has long beenthought to be enhanced by filling the defect with various bone derivedor bone-related synthetic particulates. Gerber in German PatentApplication DE 100 60 036 describes a “remodeling” mechanism whereinbone is resorbed and replaced by osteoclasts by processes termed“osteogenesis”, “osteoconduction” and “osteoinduction”. Gerber describesosteoconduction as bone growth arising from bone tissue that is presentalong a leading structure thereof; osteoinduction as a stimulation ofdifferentiation of non-bone cells to form osteoblasts; and osteogenesisas a new formation of bone from vital, transplanted bone cells.

[0005] Gerber notes that resorbability is an essential requirement for amaterial that is to participate in remodeling and be replaced by naturalbone within a certain time without an inflammation reaction thatinhibits formation of tissue.

[0006] Of the useful bone particulates, autologous derived material,while effective and safe, is of impractical availability generally.Allogenic material is readily available and, alternatively, xenogeneicbone sources are utilized as well. Synthetic materials, principallyhydroxyapatite are also available.

[0007] The various particulate bone derived materials may includenaturally occurring organic components that function to induce andmediate replacement bone growth. However, there are concerns forbiocompatibility and safety in allowing organic components to remain inthe bone particulate material. Hence, the bone particulate may betreated by a sintering process to reduce such risks. Alternatively, thebone particulate source material may be replaced by a completelysynthetic hydroxyapatite material that includes no organic residue. Thedifficulty arising for synthetics is that the resulting material may notresorb or otherwise lacks activity in the remodeling process.

[0008] Some researchers have focused upon providing bone or substituteparticulates that have porous structures that enhance bone growth orintegration. Thus, Ewers et al in U.S. Pat. No. 4,770,860 describe aresorbable porous hydroxyapatite material, derived from alime-containing algae by means of a hydrothermal process in the presenceof phosphates. In Ewers et al U.S. Pat. No. 6,428,803, thehydroxyapatite material is provided in the form of a gel obtained by aunique sol-gel process.

[0009] In the previously mentioned German Patent Application DE 100 60036, Gerber describes a resorbable bone replacement material based uponcalcium phosphates wherein the material is characterized by a “loose”crystal structure. The structure further includes various sizedinterconnecting pores that encourage ingrowth of collagen fibers toinitiate the remodeling process.

[0010] Formulations thought to enhance repair of bone tissue may includebone growth agents. Bhatnagar in U.S. Pat. No. 5,635,482 describes asynthetic collagen-like agent that mimics autogenous cell attachmentfactors that promote bone growth. Bhatnagar identified and synthesized afifteen amino acid sequence of Type I collagen that promotes migrationof reparative cells from surrounding tissues; directs cell attachmentand oriented migration; and facilitates a biomimetic environment forbone generation. These and related polypeptide materials, called P-15,are bound to a particulate hydroxyapatite which may be a natural,microporous xenogeneic bone mineral, such as OsteoGraf® N-300manufactured by Dentsply Friadent CeraMed of Lakewood, Colo. In orderfor the P-15 cell binding poly peptide to be active, it must be boundirreversibly to the particulate. Bhatnagar teaches that the resultingdry particulate matrix including P-15, trade marked PEPGEN P-15® BoneGraft and sold by Friadent CeraMed may be combined with a carrier suchas PBS or a hydrogel for placement, for example, in an intrabony defectin a tooth supporting structure.

[0011] The literature includes a number of formulations including other“growth factors” that function differently from P-15, in that thefactors are not bound to the particulate but in solution. Radomsky inU.S. Pat. No. 5,942,499 and related patents claim increasing bone growthrate or magnitude directly, without the presence of active boneparticulates or the like, by combining bFGF with hyaluronic acid.Radomsky distinguishes his formulation from the known effectiveness ofdemineralized bone matrix (DBM) alone or DBM in combination withhyaluronic acid. Radomsky claims enhancing bone repair, depending solelyupon the combination of bFGF with hyaluronic acid to promote growthamount. Gertzmann et al in U.S. Pat. No. 6,030,635 utilizes an allogenicbone particulate that is demineralized comprising essentially collagen,further containing active “bone morphogenic proteins” (BMP), wherein theresulting formulation is said to be osteoconductive and osteoinductive,with the DBM particulate being remodeled into natural bone. Theformulation includes less than about 50% by weight DBM suspended inhyaluronic acid, having a molecular weight of 7×10⁵-3×10⁶ daltons, toform a hydrogel that is a malleable putty. Higher concentrations of DBMin the Gertzmann formulation result in poor formability, too grainy andtoo dry for convenient placement.

[0012] In general, formulators of bone treatment materials have directeda great deal of effort to improve handling characteristics throughselection of an appropriate carrier for delivering the bone repairmaterial to the defect site. It is desirable that the bone repairmaterial be easily placed, but not be allowed to migrate from thedefect. In addition, and primarily, bone formation must not be inhibitedby the carrier. That is, the carrier materials for the bone repairmaterial must be biocompatible and not interfere with the mediated boneformation, while helping provide adequate spacing between the repairmaterial particulates to allow for cell and vascular infiltration. Thecarrier material should biodegrade and be resorbed. However, too fast adegradation rate is not preferred since cellular and vascularinfiltration cannot develop. Too slow of a resorption rate alsointerferes with cellular migration, vascular penetration and boneformation.

[0013] As described by Bhatnagar, as well as the others cited above,preferred carriers are hydrogels that incorporate the bone particulateand any growth enhancing agent. Preferred hydrogels includepolysaccharides, particularly those of high molecular weight, preferablygreater than 10⁶ daltons. A most particularly preferred carrier ishyaluronic acid and its derivatives. While much of the prior systemshave required injectability as a key handling characteristic,compositions that have a putty consistency are particularly useful intreating periodontal and related bone loss defects.

[0014] In a typical periodontal surgical bone repair procedure ormethod, an incision is made in the gum tissue to expose a bone defectadjacent to a tooth root. Once the defect and root are debrided, a bonerepair material, such as the aforementioned PEPGEN P-15 bone graftmaterial, suspended in a suitable carrier is placed. The gum tissue isthen closed, maintaining the repair material in place. See Bowen et alin “Comparison of Decalcified Freeze-Dried Bone Allograft and PorousParticulate Hydroxyapatite in Human Periodontal Osseous Defects”, J.Periodontology (May 1989). Optionally, a barrier material may beutilized to retain the repair formulation in contact with the defect.

[0015] There remains a need for bone repair treatment formulations thatcomprise a putty consistency with high concentrations of resorbable boneor bone-like particulate in a high concentration carrier that whenapplied to the defect site remains adhered thereto without migration orexcessive expansion.

SUMMARY OF THE INVENTION

[0016] It is an object of the invention to provide a bone repairmaterial or composition that includes: a porous, resorbable particulate,derived from bone or bone-like hydroxyapatite or synthetichydroxyapatite; and a resorbable carrier gel component, for placing in abony defect wherein bone repair is facilitated, said bone repairmaterial of a putty-like consistency. Preferably the bone repairmaterial composition or formulation comprises a high concentration ofparticulate material, comprising 30-75 weight percent of the puttydepending upon the particulate density, requiring a high concentrationof carrier component to maintain said particulate in the putty.

[0017] Further, the invention provides a bone repair formulation thatdoes not significantly expand in contact with biological fluids, doesnot migrate from the site of application and does not interfere withbone formation.

[0018] It is an object of the invention to provide a bone repairformulation that is moldable and adhesive at room temperature, maintainsthe bone repair particulate in suspension for sufficient time to enhancebone growth, is not immediately solublized or swelled by biologicalfluids and does not dry out too rapidly. The bone repair formulation ofthe invention is preferably in the form of a putty that may be trowelledinto place using a spatula, placed by syringe or even hand molded intothe bony defect to be repaired. The putty maintains the bone repairparticulate in a suspension matrix and does not migrate from the defectplacement.

[0019] A preferred bone repair or implant material of the inventionparticularly useful for repairing periodontal defects, in addition toincluding a bone-like hydroxyapatite mineral particulate, preferablyincludes a P-15 polypeptide synthetic biomimic of Type I collagen bonegrowth enhancer, having at least one of the peptide sequences describedin Bhatnagar, U.S. Pat. No. 5,635,482, bound to said particulate.

[0020] The formulation of the invention includes a carrier component forsuspending said particulate mixture, forming a moldable, putty-likeformulation for placing in a periodontal bone defect, wherein bonegrowth repair is facilitated. A preferred carrier component is apolysaccharide such as hydroxylpropyl cellulose or methyl cellulose orthe like. Particularly preferred are mucopolysaccharides, such ashyaluronic acid and its derivatives. The carrier selected is of highmolecular weight and in a sufficiently high concentration in the puttyto suspend the high concentration of particulate in the putty, saidconcentration preferably 45-64 mg/cc.

[0021] In a most preferred formulation, the collagen poly peptidetreated particulate comprises about 55% by weight of the formulation and45% by weight of a hyaluronic acid gel carrier of sufficient molecularweight, preferably 0.7-2×10⁶ daltons, that the formulation forms aviscous, moldable putty. A key advantage of the carrier is that theparticulate, once placed, remains uniformly suspended, does not settleor separate substantially from the carrier, does not significantly swellafter placement in a bone defect repair and where particles do notmigrate away from putty.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The invention is a composition or formulation of a bone repairmaterial and a method of using the material to repair defects in bones.It is particularly suited for use in enhancing regeneration of bone andrepairing dental bony defects such as in treating periodontal diseasewhere alveolar bone is eroded and support for adjacent teeth has beendestroyed or is seriously threatened. It is further useful in augmentingbony defects of the alveolar ridge, filling tooth extraction sites, andsinus elevation grafting.

[0023] The invention provides a bone repair or graft formulation thatincludes a porous, resorbable particulate, derived from bone orsynthetic or natural bone-like material, that forms a matrix structureto enhance and temporarily support new bone growth. The particulatematerial may be derived from an allograft, xenogeneic or other naturalbone-derived material, for example. A preferred xenogeneic material isany of the porous, resorbable bone graft materials, such as sold underthe PEPGEN P-15® or OsteoGraf® marks and manufactured by DentsplyFriadent CeraMed, that are anorganic, natural, microporous,bovine-derived bone mineral. The PEPGEN P-15® bone graft materialtypically has a particle size of 250-420 microns. Over time, theparticulate material is resorbed and remodeled into natural bone,remaining only temporarily to provide a structure that is completelyintegrated by new bone tissue.

[0024] In another embodiment, the porous resorbable bone-like materialis ALGIPORE® or ALGISORB® hydroxyapatite, also sold by Dentsply FriadentCeraMed, derived from lime-containing algae in accord with Ewers, et alU.S. Pat. Nos. 4,770,860 and 6,428,803, the disclosures of which areincorporated by reference in their entirety.

[0025] The invention preferably provides a bone growth enhancingcomposition, most preferably comprising the P-15 polypeptide sequencesdescribed by Bhatnagar in U.S. Pat. No. 5,635,482 and its continuationsand divisions, wherein P-15 is a synthetic biomimetic of a fifteen aminoacid sequence of Type I collagen that is uniquely involved in thebinding of cells, particularly fibroblasts and osteoblasts. The P-15material promotes the migration of reparative cells from surroundingtissues; directs cell attachment and oriented migration; and facilitatesa biomimetic environment for bone generation. Any of the syntheticpolypeptide sequences described or claimed in U.S. Pat. No. 5,635,482and its various continuations/divisions thereof are suitable, and theirdisclosures are incorporated herein by reference.

[0026] An effective formulation includes a high concentration ofparticulate for maintaining the formulation at the defect site. A highconcentration of particulate results in higher bone formation. Moreparticulate retained at a site increases the concentration of bonegrowth enhancing agent, such as P-15 at the defect site, since P-15 isbound to the particulate. The concentration of PEPGEN P-15 may range800-960 mg/cc, including about 880 mg/cc for the preferred 55% by weightcomposition where PEPGEN P-15 is the putty particulate.

[0027] There is a direct relationship between the weight percentage ofparticulate present in the applied putty formulation and the bulkdensity of the particulate. A successful putty formulation, for example,includes 55% by weight of the preferred PEPGEN P-15 composition having aparticulate component of OsteoGraf®/N 300 having a bulk density of 1.2g/cc. A successful putty formulation, including ALGIPORE particulate,having a bulk density of 0.5 g/cc, comprises 35-40 weight percentALGIPORE particulate.

[0028] A key element of the invention is that a carrier is provided, incombination with a desired amount of bone particulate, wherein a puttyis formed that is moldable, easy to handle and place in a dental bonydefect. Especially, the putty upon placement remains substantially fixedand adhered in place without migrating into adjacent tissues. Thecarrier is resorbed after a period of time but maintains its structuralintegrity long enough to help provide structure for placement of thegraft and for bone to form. The carrier material must be biocompatible,even at relatively high concentrations that are necessary to achieve aformulation that does not excessively change dimensions. Dimensionalstability of the formulation; i.e., neither significantly expanding norshrinking, is also a key feature of the invention.

[0029] Preferred carrier compositions are polysaccharides, includingmucopolysaccharides. Of the polysaccharides, hydroxylpropyl cellulose(HPC) and methyl cellulose are suitable. Of the mucopolysaccharides,hyaluronic acid and its derivatives are preferred. Useful carriers aretypically of high molecular weight. The preferred hyaluronic acids andderivatives typically are 0.7-2.0×10⁶ daltons, preferably 1.0-1.8×10⁶daltons.

[0030] The carrier component selected must be present in a relativelyhigh concentration to contain the desired high concentration ofparticulate and yet maintain desired putty characteristics and retainthe particulate at the defect site. Concentrations of the preferredhyaluronic acid are on the order of 45-64 mg/cc in the putty. Suchhigher carrier concentration forms a preferred putty even at 55 weightpercent or greater for the PEPGEN P-15 particulate, in contrast to priorart formulations which are too dry or grainy when approaching 50%particulate of comparable density.

[0031] The dental bone augmentation and bone repair putty of theinvention may be utilized in treating sinus elevation defects,extraction sites, bone loss around implants and to support implantplacement, extraction site ridge preservation, repair periodontalintrabony defects, pre-existing defects around implants, ridgeaugmentation, ridge onlay, repair furcation defects, to cover exposedimplant surfaces or threads, or to repair an edentulous site tofacilitate implant acceptance.

[0032] For example, a sinus elevation defect is a lack of available boneheight in the maxillary posterior, due to bone resorption after toothloss. Grafting the floor of the sinus increases available bone heightallowing for ideal implant placement. An incision is made from theposterior tuberosity slightly palatal to the crest of the ridge to thecanine area exposing the lateral antral wall. A lateral window iscreated through the cortical bone and then the Schneiderian membrane isgently lifted and positioned superiorly, creating access for recipientgraft. PEPGEN P-15 graft putty material of the invention is packed intothe subantral space anteriorly, medially and posteriorly. The highparticle concentration within the putty of the invention assists inlifting the Schneiderian membrane. The flap is repositioned and sutured.Membrane use is at the discretion of the clinician.

[0033] In treating extraction socket defects, a tooth is atraumaticallyextracted, preserving the bony socket walls as much as possible.Thorough debridment, curettage, irrigation and aspiration of the socketis essential and all bleeding should be under control. PEPGEN P-15 graftputty of the invention is then placed into the lower portion of thesocket and gently packed to insure intimate contact between the graftmaterial and the bony walls. The remainder of the socket is then filledto the height of the alveolar crest. PEPGEN P-15 putty of the inventionprovides spacing to insure vascularization through the graft. Primaryclosure is preferable but not essential to the success of the graft. Acontainment device or membrane may be placed over the graft to containthe material in the socket. A simple suture (4 to 6 point closure)assists in healing.

[0034] Deficient alveolar ridges require augmentation to provideadequate bone for implant placement. An incision is created over thedeficient area and the ridge exposed. After elimination of allperiosteum and soft tissue, the cortical bone should be prepared toreceive the graft material. Preparation includes cortical fenestrationto allow bleeding and the release of bone marrow. PEPGEN P-15 graftputty of the invention is gently packed onto the ridge and approximatedover the deficient bony structure. The flap is repositioned over thegraft and the primary closure of the tissue completed. Membrane use isat the discretion of the clinician.

[0035] Endosseous implants must be stable in the bony ridge and exposureof the implant through the bone is detrimental to the success of theimplant. If a portion of the implant is exposed by a dehiscence defect,for example, through the bone, bone replacement graft material can beused to repair the site and regenerate new bone to cover the implant.Incisions are made through the soft tissue to expose the dehiscence.Depending upon the surface coating of the implant, detoxification of theimplant may be necessary to thoroughly clean and prepare the implant toreceive the graft. PEPGEN P-15 graft putty of the invention is packedover the exposure of the implant to assist in bone regeneration andstability of the substrate. The flap is repositioned and primary closureis essential to the success of the graft.

[0036] The examples below further describe embodiments of thecompositions of the invention and methods of their use. The examples arenot intended to limit the scope of the invention but are illustrativeonly.

EXAMPLE 1. Hyaluronic Acid Gel

[0037] 60 grams of PEPGEN P-15® bone graft material supplied by DentsplyFriadent CeraMed of Lakewood, Colo., comprising a P-15 poly peptidesequence described by Bhatnagar in U.S. Pat. No. 5,635,482, irreversiblybound to a natural microporous, xenogenic bone material OsteoGraf®/N300, was weighed out into a container. 40 grams of hyaluronic acid gel,having a molecular weight of 7×10⁵ daltons, supplied by HyaluronCorporation of Woburn, Mass., was mixed with the PEPGEN P-15 material bymeans of a spatula to homogeneity. The resulting material is of amoldable, putty-like consistency, wherein the particulate remainssuspended in the putty gel even when spun in a centrifuge (3,000 rpm for30 minutes) The resulting putty of the 60:40 material had a density of1.664 +/−0.0533 g/cc. The concentration of hyaluronic acid component inthe putty is about 47 mg/cc, and the concentration of active PEPGEN P-15is about 960 mg/cc.

EXAMPLE 2 Hydroxylpropyl Cellulose Gel

[0038] 7 grams of hydroxylpropyl cellulose, hereinafter abbreviated HPC,having a molecular weight of about 1,150,000 daltons, supplied byHercules (Klucel, HF Pharma), was added to 93 grams of water or isotonicsaline and immediately mixed by hand. The mass was re-mixed after 2-3minutes and re-mixing was repeated until a gel was formed, which washeld overnight at 4-8° C. 55 grams of PEPGEN P-15 was added to 45 gramsof the HPC gel and mixed with a spatula until uniform. The resultingformulation was: PEPGEN P-15 particles 55.00 grams HPC 3.15 grams Wateror Isotonic Saline 41.80 grams

[0039] The resulting putty mass had a density in saline of1.647+/−0.0452 g/cc.

EXAMPLE 3 Methyl Cellulose Gel

[0040] The process of Example 2 was repeated except that methylcellulose manufactured by Dow Chemical (Methocel A, A4CP) wassubstituted. The resulting formulation was: PEPGEN P-15 particles 55.00grams Methyl Cellulose 3.60 grams Glycerol 6.75 grams Water 34.60 grams

[0041] The resulting formulation was autoclavable with no noticeablechanges in handling of original characteristics. The material did notsubstantially expand in PBS or water.

EXAMPLE 4 Hyaluronic Acid Gel

[0042] The method and formulation of Example 1 was repeated except thatPEPGEN P-15 graft comprised 55% by weight and a hyaluronic gel ofgreater MW comprised 45% by weight of the formulation. To make the gel,92% sodium phosphate buffer was blended together with 8% hyaluronate byweight to homogeneity. To make 1 cc of putty, 0.55 grams of PEPGEN P-15was thoroughly mixed with 0.45 grams of hyaluronic acid gel. A preferredhigh molecular weight hyaluronic acid of 1.2-1.7×10⁶ daltons wasemployed, resulting in a concentration of about 57 mg/ml. Theconcentration of PEPGEN P-15 was about 880 mg/cc in the putty.

EXAMPLE 5 Hyaluronic Acid Gel/ALGIPORE particulate

[0043] 0.40 grams of ALGIPORE bone graft particulate, supplied byDentsply Friadent CeraMed of Lakewood, Colo., comprising the P-15peptide sequence of Example 1 bound to the ALGIPORE particulate wasmixed with 0.60 grams of a gel comprising a hyaluronic acid, prepared asdescribed in Example 4 and having a molecular weight of 1.2-1.7×10⁶daltons. Two sizes of ALGIPORE were tested: 0.3-0.5 mm and 0.5-1 mm. Theconcentration of ALGIPORE P-15 in the putty was 440 mg/cc for the0.3-0.5 cc size and 480 mg/cc for the 0.5-1.0 cc size. The concentrationof hyaluronic acid component in the putty was about 53 mg/cc for the0.3-0.5 cc size and for the 0.5-1.0 cc size. The ALGIPORE componentcomprised 40 percent by weight of the putty, the formulation comprising:ALGIPORE P-15 Particulate 0.400 grams Hyaluronic Acid 0.048 grams 10 mMSodium Phosphate 0.552 grams

EXAMPLE 6 Carboxymethyl Cellulose Gel

[0044] A gel comprising carboxymethyl cellulose (CMC), supplied byHercules (Aqualon 7HFPH) having a MW of about 700,000 daltons and aviscosity of 1500-2500 cp, glycerol and water of the followingcomposition was formed to make a carrier gel of a commercial bone graftmaterial. 37.5 grams of PEPGEN P-15 graft was added to 62.5 grams of theCMC gel and mixed until a homogenous blend resulted, yielding about 100grams of a PEPGEN P-15® Flow™ product. The resulting formulation was:PEPGEN P-15 Particulate 37.50 grams CMC 1.97 grams Glycerol 9.08 gramsWater 51.45 grams

EXAMPLE 7 Bench Top Evaluation of Handling

[0045] Samples of the invention were formulated as described in theexamples above, having the compositions shown in the table below. Theseputties were evaluated by a panel of clinicians for handlingcharacteristics. Table 1 shows the reported average scores. Example 4having the highest molecular weight of the hyaluronic acid component of1.2-1.7×10⁶ daltons and the highest hyaluronic acid concentration wasdeemed to have the most preferred handling characteristics of thesamples tested. TABLE 1 Handling Characteristics Particulate¹ CarrierGel Putty Bone Material Material, % Description/Evaluation² Examples # %by weight by weight gel Moldability Cohesiveness Stickiness 1 60.0% HY³,40.0% 3.0 2.7 2.7 2 55.0% HPC, 45.0% 2.0 2.3 3.0 4 55.0% HY, 45.0% 3.03.0 3.0

EXAMPLE 8 Dog Study to Evaluate Handling and Efficacy—Extraction Sockets

[0046] A 21.8 kg female dog approximately 1-2 years old was conditionedand approved for use by the USDA. The lower right quadrant of the jawwas anesthetized with 2% xylocaine. Sucular incisions were made on P2, 3and 4 teeth. Each crown was sectioned with a fissure bur and the threeteeth were extracted. The tissue was released on the lingual and buccalsides. Bleeding in the site was controlled with sterile gauze and thegrafting material was tapped into the extraction socket to the height ofthe crest of the bone. The putty formulations described in Example 7were employed to fill the extracted tooth sockets. Putty Example 1 waspacked into P4 anterior and distal. Putty Example 2 was packed into P3anterior and posterior.

[0047] After up to 30 minutes the filled socket was observed forexpansion. Thereafter the filled socket defect was closed by suture.

[0048] In a second dog, identically prepared to the first, putty Example4 was packed into P4 anterior and distal. After fifteen minutes, nosignificant expansion of the graft was observed. The defect was thenclosed by suture.

[0049] The time elapsed until any noticeable expansion adjacent thesocket for the examples was observed and is reported in Table 2. TABLE 2Observations of Graft Expansion Time elapsed until noticeable Volumeexpanded after 15 Formulation, Carrier expansion in socket, minutesminutes Example 6, CMC 2-3 30-40%  Example 1, HY (7 × 10⁵ MW) 10  25%Example 2, HPC (1.1 × 10⁶ 15 5-10% MW) Example 4, HY (1.2-1.7 × 10⁶ 155-10% MW)

[0050] It is noted that the extraction socket model in the dog ischaracterized by elevated blood flow at high hydrostatic pressure whichhighlights the benefits of lower expansion. The low expansion benefit,which is a key feature of the invention, is also useful at other dentalbone graft treatment sites. For example, in ridge onlays, the preferredputty of Example 4 does not expand while Putty from Example 1 doesexhibit expansion.

[0051] The following observations were made: Putty from Example 1—Thematerial accepted being in the bloody site and was able to bemanipulated with surgical instruments and sterile, dry gauze. There wasalso minimal particle displacement. Putty from Example 2—This materialdid not hold together as well in the defect. However, it could be piecedtogether easily. The product was amenable to manipulation withinstruments and sterile, dry gauze. The graft of Example 6 including aCMC carrier, known in the prior art, expands substantially and quicklyin contrast to the hyaluronic acid and HPC carrier grafts which did notswell substantially and was much slower to show expansion. The preferredformulation of Example 4, including a high molecular weight hyaluronicacid gel carrier also exhibited insubstantial expansion.

[0052] The graft sites were examined histologically after 2 and 5 weeks.Block tissue samples were placed in vials containing 10% zinc formalinand processed including decalcification, embedding in paraffin,sectioning and staining with hematoxylin and eosin. The histologicalsections were evaluated subjectively for bone formation. Excellent,good, fair and poor ratings were applied for the speed and amount ofbone repair in sockets and the interaction of the graft material withthe healing tissues. The results are reported in Table 3. TABLE 3Observations of Bone Repair Putty Examples 2 weeks 5 weeks #1 Fair Good#2 Poor Fair #4 Fair Good DBM Poor N/D

[0053] Putties of Examples 1 and 4 containing high amounts ofparticulate graft material in hyaluronic acid gel produced better bonethan other compositions. Specifically, these preferred formulationsproduced faster and more bone than the “DBM” formulation ofdemineralized allograft bone particulate suspended in a 2% hyaluronicacid/saline gel, described by Gertzmann in U.S. Pat. No. 6,030,635.

EXAMPLE 9 Dog Study to Evaluate Handling in Ridge Onlay/Flap Model

[0054] Dogs were prepared in a manner similar to Example 8. In a firstdog, the jaw site was anesthetized with 2% xylocaine. A beveled incisionwas made distal of C to mesial of P4. Vertical incisions were made and afull thickness flap was reflected. A tissue bur was utilized toperforate the cortical plate.

[0055] Putty #1, having the composition of Example 1 described above,was molded to a thickness of 6 mm and placed where it readily adhered aspositioned. The flap was closed with 4-0 vicryl. Upon the first centersuture, some excess material extruded out through the distal woundopening, which was thereafter sutured closed. After 10-15 minutes, theflap was reopened and the condition of the material observed. Thematerial remained as placed and there was minimal migration and particleloss. Some expansion was observed.

[0056] Putty #2, having the composition of Example 2 described above,was molded to a thickness of 6 mm deep and placed where it readilyadhered. The flap was closed with 4-0 vicryl. Upon the first centersuture, the material did not extrude out through distal wound opening.After 10-15 minutes, the flap was reopened and observed to have remainedas placed with minimal migration and particle loss. No substantialexpansion was observed.

[0057] In a second dog, identically prepared as the first, the preferredputty #4, having the composition of Example 4 above, was molded to thetop of exposed bone. Upon flap closure the material did not extrude fromthe distal openings. After 10 minutes the flap was reopened and thematerial was observed to have remained as placed. There was minimalparticle migration or loss. No substantial expansion was observed.

EXAMPLE 10 Dog Study to Evaluate Handling in Defect Around Implant

[0058] Dogs were prepared in a manner similar to Example 8. In a firstdog, the jaw area was anesthetized with 2% xylocaine. Teeth wereextracted from the lower right quadrant. A buccal dehiscence or defectwas created with a fissure bur and ronjour in all three distal sockets.The sockets were cleaned, irrigated and aspirated. A Calcitekhydroxyapatite coated implant cylinder (4×10 mm) was placed. Implantosteotomy sites were created in the distal sockets of each tooth site.

[0059] Putty #2, having the composition of Example 2 above, was placedinto P4 posterior. The material broke apart during placement, but waseasily reformed. The putty was in contact with irregularities of socketand implant. The putty maintained the newly formed buccal plate.

[0060] Putty #1, having the composition of Example 1 above, was placedinto P3 posterior. The material handled well during placement and was incontact with irregularities of socket and implant. The putty maintainedthe newly formed buccal plate.

[0061] In a second dog identically prepared as the first, the preferredputty, having the composition of Example 4 above, was placed into bothP2 and P3 posteriors. The material handled well during placement and wasin contact with irregularities of socket and implant. The puttymaintained the newly formed buccal plate. In addition, no particlemigration or expansion was observed.

EXAMPLE 11 Bulk Density and Particulate Concentration

[0062] The following commercially available bone-derived particulatematerials were placed into a preferred HPC or the preferred hyaluronicacid gel carrier: Bio-Oss, OsteoGraf/LD, PEPGEN P-15, (OsteoGraf/N-300),OsteoGraf/D and ALGIPORE. Each of the particulate materials was added tothe gel carrier until the desired putty consistency was achieved. Theparticle bulk density and putty particulate concentration required toreach the desired putty consistency is shown below: % (w/w) Particulateof Putty Bone Graft Particulate Formulation Bulk Particulate Density(g/cc) Bio-Oss* 30 0.5 OsteoGraf/LD** 40 0.8 PEPGEN P-15** 55 1.2(OsteoGraf/N-300**) OsteoGraf/D** 75 2.2 Algipore** (0.3-0.5 mm) 35-400.5 Algipore** (0.5-1.0 mm) 35-40 0.6

[0063] The table shows that there is a positive relationship betweenoptimal particulate percentage to make a putty formulation and theparticulate bulk density.

[0064] The Bio-Oss material manufactured by OsteoHealth is an anorganicbovine mineral of 0.25-1.00 mm derived from cancellous bone that is moreporous and less dense than PEPGEN P-15 graft particulate. A 30% (w/w)composition of Bio-Oss with HPC gel or the preferred hyaluronic acidcomposition formed a consistency similar to the preferred putty of 55%PEPGEN P-15. A 45% Bio-Oss containing putty was too crumbly and notpreferred. A 25% Bio-Oss containing putty was too thin to be moldable.

[0065] For PEPGEN P-15 graft particulate putties formed with the HPC orhyaluronic acid carrier gel, 40%-45% PEPGEN P-15 containing formulationhad a density of 1.4 g/cc and was not of a putty consistency. At 50%,the consistency was more like a putty. A preferred formulation and puttyconsistency comprises 55% by weight and had a density of 1.5-1.6. Apreferred putty including ALGIPORE had a density of 1.1 g/cc for the0.3-0.5 or the 0.5-1.0 mm size particles.

[0066] Various modifications and alternations of the above embodimentswill be apparent to those skilled in the art without departing from thescope and spirit of the invention. It should be understood that thisinvention is not limited to the illustrative embodiments set forthabove.

What is claimed is:
 1. A bone repair material, comprising: a porous,resorbable particulate derived of anorganic bone mineral or naturalbone-like mineral or synthetic hydroxyapatite; and a resorbable carriergel component for suspending said particulate, forming a putty-likeformulation, for placing in a bony defect, said gel component having asufficiently high molecular weight and concentration in the puttywherein concentration of the particulate material is sufficiently highsuch that bone repair is facilitated while migration and expansion ofsaid material is minimized.
 2. The bone repair material of claim 1wherein said resorbable particulate is bovine-derived having a particlesize range of 250 to 1000 μm.
 3. The bone repair material of claim 1wherein said resorbable particulate is a porous hydroxyapatite derivedfrom lime-containing algae, having a particle size range of 300-1000 μm.4. The bone repair material of claim 1, wherein said carrier gelcomponent comprises a polysaccharide.
 5. The bone repair material ofclaim 4, wherein said carrier material component is hyaluronic acid orits derivatives, or hydroxylpropyl cellulose or mixtures thereof.
 6. Thebone repair material of claim 5, wherein said carrier gel component ishyaluronic acid or its derivatives having a molecular weight of0.7-2.0×10⁶ daltons and a final concentration of 45-64 mg/cc in theputty.
 7. The bone repair material of claim 1, further comprising asynthetic biomimetic, polypeptide sequence of Type I collagen, having atleast one of the poly-peptide sequences as claimed in U.S. Pat. No.5,635,482, bound to said particulate.
 8. A bone repair material fordental bone repair procedures, comprising: a porous, synthetic,resorbable, bone-like hydroxyapatite or anorganic bone derivedparticulate, in an amount of about 30-75 weight percent of saidmaterial; and a hyaluronic acid gel in an amount of about 25-70 weightpercent of said material, wherein said material is a moldable, cohesiveputty for application to bony defects, said amount of particulatepresent dependent upon its density.
 9. The bone repair material of claim7, wherein said particulate has a bulk density of 1.1 to 1.3 g/cc andthe putty composition comprises about 50-60 weight percent particulateand about 40-50 weight percent hyaluronic acid gel.
 10. The bone repairmaterial of claim 7, wherein said bone repair material comprises about55 weight percent particulate and about 45 weight percent hyaluronicacid gel.
 11. The bone repair material of claim 7, wherein saidparticulate has a bulk density of 0.45 to 0.65 g/cc and the puttycomposition comprises 35-40 weight percent particulate and 60-65 weightpercent hyaluronic acid.
 12. The bone repair graft material of claim 4,wherein said carrier is a hydroxylpropyl cellulose or methyl cellulosegel forming a moldable, cohesive putty.
 13. The bone repair material ofclaim 8 comprising at least one of a P-15 polypeptide sequence ofcollagen as claimed in U.S. Pat. No. 5,635,482, bound to xenogeneic bonemineral particulate of about 200-500 mm in diameter, suspended in saidgel carrier, said material having a putty-like consistency.
 14. The bonerepair material of claim 3 comprising at least one of a P-15 polypeptidesequence of collagen as claimed in U.S. Pat. No. 5,635,482 andcontinuations thereof, bound to porous hydroxyapatite derived from limecontaining algae of about 300-1000 μm in diameter suspended inhydroxylpropyl cellulose or hyaluronic gel carrier, said material havinga putty-like consistency.
 15. A method of treating bone loss and repairsthereof, comprising: making an incision in gum tissue adjacent a bonydefect and reflecting a flap of said tissue to expose said defect;debriding said defect and adjacent tooth roots at said defect: placingthe bone repair material of claim 1 in said defect; and closing saidtissue flap to cover the treated defect.
 16. The method of claim 15,wherein placing the repair material is by spatula, instrumentation,hand, or injection.
 17. The method of claim 15, wherein said bone repairmaterial comprises said is a P-15 poly peptide sequence of collagenbound to xenogeneic bone material particulates, suspended in anhydroxylpropyl cellulose (HPC) or hyaluronic acid or derivatives gelcarrier, said material having a putty-like consistency.
 18. The methodof claim 15, wherein said bone loss and repairs comprise placing saidbone putty in a defect on the alveolar ridge, in an extraction socket,to correct sinus elevation defects or to repair an implant dehiscence.19. The bone repair material of claim 7, wherein the concentration ofPEPGEN P-15 in the putty at least about 800 mg/cc.